ABSTRACT HER2-positive disease, which comprises 20% of all breast cancers, is among the most aggressive but treatable forms. Outcomes for HER2-positive patients have been transformed by the development of several highly effective HER2-targeting agents that are given broadly for stages I-IV HER2+ breast cancer either as single agents or as dual HER2-targeting. These drugs have reduced death rates from this disease by nearly 40%, however come at a high financial cost ? all HER2-targeted drugs individually cost at least $100,000 per year. We also clearly overtreat many of the approximately 40,000 non-metastatic patients diagnosed with HER2-positive breast cancers in the U.S. each year. Most of the treatment regimens used in stages I-III HER2- positive breast cancer include polychemotherapy with 2-3 cytotoxic drugs plus 1-2 HER2-targeted drugs given for 1 year. Genomic studies from large randomized trials provide opportunities for improvement. Several studies have found that tumor and microenvironmental influences are major contributors to variability in response and outcome. RNA- and DNA-based studies from CALGB 40601 and other neoadjuvant trials of HER2-targeting agents suggest that tumor intrinsic molecular subtype and immune cell activation are at least as important as treatment type in determining outcome and can identify tumors that respond best to single or dual HER2- targeting. These studies suggest a way to more thoughtfully and rationally treat HER2-positive breast cancer patients, but we must do this collaboratively and comprehensively. We propose to collectively integrate and analyze the clinical, gene expression, gene aberration, response to therapy, and outcomes data from more than 1500 women participating in multiple randomized neoadjuvant clinical trials of HER2-targeted therapy. We will examine the role of tumor and microenvironmental factors in determining response to HER2-targeting, relationship of pathologic complete response to outcome, and the biology of residual disease after dual or single HER2-targeting in HER2-positive breast cancer.